Psoriasis is a cutaneous inflammatory disorder characterized by epidermal keratinocyte hyperproliferation. Several theories have been proposed regarding the molecular nature and etiology of psoriasis. Factors that have been invoked to cause or promote psoriasis include genetic composition, immune functions, epithelial functions, proliferative and differentiation signals, and/or environmental factors. See Nickoloff et al. (2000) Exp Dermatol 9:359-375. The disparate explanations offered by such theories have directed the development of accordingly different therapeutic strategies.
A prevailing view holds that skin disorders such as psoriasis can develop by an initial immune response to a microbial agent that subsequently evolves to a self-perpetuating auto-immune disease. Thus, a current strategy for therapeutic treatment of psoriasis comprises disruption or suppression of the immune response. In particular, drug design approaches are directed at disruption of various aspects of T-cell function, including mechanisms of recruitment, cell-cell interaction, and cytokine production. See Barker (1998) Hosp Med 59(7):530-533.
A second view holds that the psoriasis results from erroneous activation of an epithelial defence system. Such an abnormal defence response is characterized by the activity of superantigens and proinflammatory cytokines. This model asserts to explain the predominance of psoriasis in skin and the resemblance of psoriatic skin to bacterial infection and wound healing. In one aspect, genetic factors are implicated in abnormal epithelial responses to infectious and/or physicochemical skin insults.
A related perspective suggests that inappropriate keratinocyte proliferative and differentiation signals comprise the primary disorder of psoriasis. For example, psoriasis may result from misregulation of neutrophils, which are required for epithelial differentiation and keratinization. This developmental defect can occur in the absence of an infectious challenge.
Yet another model proposes that the interaction among epidermal factors (e.g., adhesion molecules), neuropeptides (e.g., nerve growth factor, Substance P), and T lymphocytes plays a causative role in the development of psoriasis.
Each of the afore-mentioned explanations have been accompanied by limited experimental and/or clinical data. Yet a model, and hence a therapy, that encompasses most, if not all, observations related to psoriasis remains undisclosed and unavailable in the art.
What is needed, then, is a comprehensive model of psoriasis, and more generally, of immune disease and skin disease. Such an understanding can improve current diagnostic and therapeutic strategies for treating psoriasis and other disorders. To this end, the inventors of the present invention suggest that psoriasis is an immunologically mediated response of the epidermis to cope with microbial antigens of external or circulating form. Otherwise stated, psoriasis is the result of a continuous and useful response of the skin to the presence of microbial antigen in the skin. This model reconciles several contrasting views summarized above, and, as will be evident from the disclosure herein, presents a novel approach for treating systemic and autoimmune diseases.
Further, the present invention provides methods for facilitating diagnosis of a systemic or autoimmune disorder by detecting an immune product in a biological sample, particularly at a basement membrane of a biological sample. Further provided are methods for treating a systemic disease (including but not limited to a systemic microbial infection or an autoimmune disease) in a subject by inducing the production of or otherwise providing an autoantibody that recognizes a skin basement membrane element.